|
【结 构 式】 
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【分子编号】12313 【品名】diethyl succinate 【CA登记号】123-25-1 |
【 分 子 式 】C8H14O4 【 分 子 量 】174.19676 【元素组成】C 55.16% H 8.1% O 36.74% |
合成路线1
该中间体在本合成路线中的序号：(XXXIX)The intermediate trans-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetra-hydronaphtho[2,3-d][1,3]benzodioxole-6-carboxylic acid ethyl ester (XI) has been obtained by several different ways: (a) The condensation of benzophenone (XXXVIII) with diethyl malonate (XXXIX) by means of t-BuOK gives the alkylidenemalonate (XL), which is hydrogenated with H2 over Pd/C to the alkylmalonate hemiester (XLI). The reaction of (XLI) with acetyl chloride affords the mixed anhydride (XLII), which is finally cyclized to the target (XI) by means of SnCl4. (b) The cyclization of the malonic ester derivative (XLIII) by means of Ti(CF3--CO2)3 gives the 5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho [2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLIV), which is finally oxidized and decarboxylated with NBS and NaOH in methanol to afford the target intermediate (XI). (c) The cyclization of the benzylidenemalonate (XLV) with the aryllithium derivative (XLVI) gives the 8-methoxy-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,6-dicarboxylic acid dimethyl ester (XLVII), which is demethylated with TFA and oxidized with CrO3 and pyridine to the target compound (XI). (d) The cyclopropanation of the chalcone (XLVIII) with (ethoxycarbonyl) (dimethylsulfonium)methylide (XLIX) gives the cyclopropanecarboxylate (L), which is finally rearranged with BF3/Et2O to the target intermediate (IX).
| 【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XI) | 34966 | ethyl (5R,6R)-8-oxo-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate | C23H24O8 | 详情 | 详情 | |
| (XXXVIII) | 34992 | 1,3-benzodioxol-5-yl(3,4,5-trimethoxyphenyl)methanone | C17H16O6 | 详情 | 详情 | |
| (XXXIX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (XL) | 34993 | (E)-4-(1,3-benzodioxol-5-yl)-3-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-3-butenoic acid | C23H24O9 | 详情 | 详情 | |
| (XLI) | 34994 | 4-(1,3-benzodioxol-5-yl)-3-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)butyric acid | C23H26O9 | 详情 | 详情 | |
| (XLII) | 34995 | acetic 3-(1,3-benzodioxol-5-yl)-2-(ethoxycarbonyl)-3-(3,4,5-trimethoxyphenyl)butyric anhydride | C25H28O10 | 详情 | 详情 | |
| (XLIII) | 34996 | diethyl 2-[2-(1,3-benzodioxol-5-yl)ethyl]-2-(3,4,5-trimethoxybenzyl)malonate | C26H32O9 | 详情 | 详情 | |
| (XLIV) | 34997 | diethyl 5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-dicarboxylate | C26H30O9 | 详情 | 详情 | |
| (XLV) | 34998 | diethyl 2-(3,4,5-trimethoxybenzylidene)malonate | C17H22O7 | 详情 | 详情 | |
| (XLVI) | 34999 | [6-(2-bromo-1-methoxyethyl)-1,3-benzodioxol-5-yl]lithium | C10H10BrLiO3 | 详情 | 详情 | |
| (XLVII) | 35000 | diethyl 8-methoxy-5-(3,4,5-trimethoxyphenyl)-7,8-dihydronaphtho[2,3-d][1,3]dioxole-6,6(5H)-dicarboxylate | C27H32O10 | 详情 | 详情 | |
| (XLVIII) | 35001 | (E)-1-(1,3-benzodioxol-5-yl)-3-(3,4,5-trimethoxyphenyl)-2-propen-1-one | C19H18O6 | 详情 | 详情 | |
| (L) | 35002 | ethyl 2-(1,3-benzodioxol-5-ylcarbonyl)-3-(3,4,5-trimethoxyphenyl)cyclopropanecarboxylate | C23H24O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The Friedel-Kraft's reaction of benzene (I) and 3,4-dichlorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3,4-dichlorobenzophenone (III), which is condensed with diethyl succinate (IV) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (V). Hydrolysis of (V) with HBr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (VII), which is converted into the corresponding acyl chloride (VIII) with refluxing SOCl2. Cyclization of (VIII) with AlCl3 in CS2 yields 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (IX), which is treated with methylamine and TiCl4 in THF affording the corresponding Schiff base (X). Finally, this compound is reduced with H2 over Pd/C in THF.
| 【1】 Kraska, A.R.; Welch, W.M. Jr.; Koe, B.K.; Harbert, C.A. (Pfizer Inc.); Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphtalenamine. EP 0030081; JP 1981086137; US 4536518 . |
| 【2】 Castaner, J.; Serradell, M.N.; Sertraline. Drugs Fut 1984, 9, 4, 277. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (II) | 26356 | 3,4-dichlorobenzoyl chloride | 3024-72-4 | C7H3Cl3O | 详情 | 详情 |
| (III) | 30578 | (3,4-dichlorophenyl)(phenyl)methanone | 6284-79-3 | C13H8Cl2O | 详情 | 详情 |
| (IV) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (V) | 30579 | diethyl 2-[(Z)-(3,4-dichlorophenyl)(phenyl)methylidene]succinate | C21H20Cl2O4 | 详情 | 详情 | |
| (VI) | 30580 | (E)-4-(3,4-dichlorophenyl)-4-phenyl-3-butenoic acid | C16H12Cl2O2 | 详情 | 详情 | |
| (VII) | 30581 | 4-(3,4-dichlorophenyl)-4-phenylbutyric acid | C16H14Cl2O2 | 详情 | 详情 | |
| (VIII) | 30582 | 4-(3,4-dichlorophenyl)-4-phenylbutanoyl chloride | C16H13Cl3O | 详情 | 详情 | |
| (IX) | 30583 | 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone; 4-(3',4'-Dichlorophenyl)-1-tetralone | 79580-19-3 | C16H12Cl2O | 详情 | 详情 |
| (X) | 30584 | N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-N-methylamine; N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine | C17H15Cl2N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 3,4-dimethoxy-2-isopropylbenzaldehyde (I) with diethyl succinate (II) by means of NaH in refluxing benzene gives 2-(2-isopropyl-3,4-dimethoxybenzylidene)succinic acid monoethyl ester (III), which is cyclized by treatment with acetic anhydride and sodium acetate in refluxing acetic acid and hydrolyzed with NaOH in refluxing methanol yielding acid (IV). The reduction of (IV) with LiAlH4 in ether affords 3-hydroxymethyl-5-isopropyl-6,7-dimethoxy-1-naphthol (V), which is hydrogenated with H2 over Pd/C in methanol with some HCl giving 3-methyl-5-isopropyl-6,7-dimethoxy-1-naphthol (VI). Thermal dimerization of (VI) by heating at 215 C yields 2,2'-bis(3-methyl-5-isopropyl-6,7-dimethoxy-1-naphthol) (VII).
| 【1】 Cashaw, J.L.; Edwards, J.D.Jr.; Studies in the naphtalene series. III. Synthesis of apogossypol hexamethyl ether. J Am Chem Soc 1957, 79, 2283. |
| 【2】 Edwards, J.D.Jr.; Total synthesis of gossypol. J Am Chem Soc 1958, 80, 3798. |
| 【3】 El-Nockrashy; J Am Oil Chem Soc 1963, 40, 1, 14. |
| 【4】 Leeson, P.; Gossypol. Drugs Fut 1979, 4, 5, 338. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 33240 | 2-isopropyl-3,4-dimethoxybenzaldehyde | C12H16O3 | 详情 | 详情 | |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 33241 | (E)-3-(ethoxycarbonyl)-4-(2-isopropyl-3,4-dimethoxyphenyl)-3-butenoic acid | C18H24O6 | 详情 | 详情 | |
| (IV) | 33242 | 4-hydroxy-8-isopropyl-6,7-dimethoxy-2-naphthoic acid | C16H18O5 | 详情 | 详情 | |
| (V) | 33243 | 3-(hydroxymethyl)-5-isopropyl-6,7-dimethoxy-1-naphthol | C16H20O4 | 详情 | 详情 | |
| (VI) | 33244 | 5-isopropyl-6,7-dimethoxy-3-methyl-1-naphthol | C16H20O3 | 详情 | 详情 | |
| (VII) | 33245 | 2-(1-hydroxy-5-isopropyl-6,7-dimethoxy-3-methyl-2-naphthyl)-5-isopropyl-6,7-dimethoxy-3-methyl-1-naphthol | C32H38O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)1) Synthesis of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine: The condensation of diethyl succinate (III) with 1-naphthaldehyde (IV) by means of sodium ethoxide in refluxing methanol gives 2-(1-naphthylmethylene)succinic acid diethyl ester (V), which is hydrolyzed to the corresponding acid (VI) with NaOH. The cyclization of (VI) with refluxing SOCl2 affords the anhydride (VII), which is treated with morpholine (VIII) in ethyl acetate, yielding 2-(morpholinocarbonylmethyl)-3-(1-naphthyl)acrylic acid (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding propionic acid (X), which is then condensed with histidine methyl ester (XI) by means of DCC and HONB as before, giving a racemic mixture that is submitted to optical resolution by repeated crystallization of its salycylic acid salt, thus yielding N-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine methyl ester (XII). Finally, this compound is hydrolyzed with NaOH and protected with tert-butoxycarbonyl anhydride to give (I).
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (III) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 12315 | diethyl 2-[(Z)-1-naphthylmethylidene]succinate | C19H20O4 | 详情 | 详情 | |
| (VI) | 12316 | 2-[(Z)-1-Naphthylmethylidene]succinic acid | C15H12O4 | 详情 | 详情 | |
| (VII) | 12317 | 3-[(Z)-1-Naphthylmethylidene]-2,5(4H)-furandione | C15H10O3 | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IX) | 12319 | (Z)-2-(2-Morpholino-2-oxoethyl)-3-(1-naphthyl)-2-propenoic acid | C19H19NO4 | 详情 | 详情 | |
| (X) | 12320 | 4-Morpholino-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (XI) | 12321 | methyl (2S)-2-amino-3-(1H-imidazol-5-yl)propanoate; Methyl-L-histidine | 1499-46-3 | C7H11N3O2 | 详情 | 详情 |
| (XII) | 12322 | methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2R)-4-morpholino-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.
| 【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034. |
| 【2】 Yamaguchi, T.; et al.; Preparation of optically active succinic acid derivatives. I. Optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid. Chem Pharm Bull 1997, 45, 9, 1518. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 41057 | 2-[(Z)-benzylidene]succinic acid | C11H10O4 | 详情 | 详情 | |
| (IV) | 41058 | 3-[(Z)-benzylidene]-2,5(4H)-furandione | C11H8O3 | 详情 | 详情 | |
| (V) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 详情 | 详情 | |
| (VI) | 41060 | (Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid | C19H23NO3 | 详情 | 详情 | |
| (VII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 41062 | 4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XI) | 41063 | (2S)-N-benzyl-2-hydroxy-2-phenylethanamide | C15H15NO2 | 详情 | 详情 | |
| (XII) | 41065 | (1S)-2-(benzylamino)-2-oxo-1-phenylethyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate | C34H38N2O4 | 详情 | 详情 | |
| (XIII) | 41064 | (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid | C19H25NO3 | 详情 | 详情 | |
| (XIV) | 17443 | (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine | 3886-70-2 | C12H13N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the S-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the R-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The Stobbe-type condensation of tetralone (I) with diethyl succinate (II) by means of potassium tert-butoxide in tert butanol and subsequent hydrolysis/decarboxylation in HOAc/HCl gives the propionic acid (III), which is asymmetrically reduced with H2 over a chiral ruthenium catalyst in methanol to afford (S)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propionic acid (S)-(IV). The cyclization of (IV) by means of PPA at 130 C provides the hexahydrophenalen-1-one (V), which by reaction with hydroxylamine is converted into the oxime (VI). The reduction of (VI) with H2 over Raney Ni in methanol yields the corresponding amine (VII), which is condensed with the piperidinium iodide (VIII) by means of K2CO3 in refluxing ethanol to afford a diastereomeric mixture from which the desired enantiomer (IX) is separated by column chromatography. A Strecker reaction of (IX) with aniline and Tms-CN in HOAc gives the anilino nitrile (X), which is finally cyclized by reaction with formic acid, Ac2O and formamide at 200 C to yield the target spiro compound. Alternatively, the anilino nitrile (X) is hydrolyzed with formic acid/Ac2O to give the formylated carboxamide (XI), which is finally cyclized with refluxing triethyl orthoformate, followed by reduction with NaBH4 in methanol.
| 【1】 Hennig, M.; Adam, G.; Wichmann, J.; Cesura, A.M.; Dautzenberg, F.M.; Scalone, M.; Jenck, F.; Rover, S.; Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic properties. Eur J Med Chem 2000, 35, 9, 839. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 51989 | 3-(3,4-Dihydronaphthalen-1-yl)propionic acid | C13H14O2 | 详情 | 详情 | |
| (IV) | 51990 | 3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]propionic acid | C13H16O2 | 详情 | 详情 | |
| (V) | 51991 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one | C13H14O | 详情 | 详情 | |
| (VI) | 51992 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one oxime | C13H15NO | 详情 | 详情 | |
| (VII) | 51993 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-amine; (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-ylamine | C13H17N | 详情 | 详情 | |
| (VIII) | 51994 | 1-ethyl-1-methyl-4-oxopiperidinium iodide | C8H16INO | 详情 | 详情 | |
| (IX) | 51995 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-piperidinone | C18H23NO | 详情 | 详情 | |
| (X) | 51996 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-anilino-4-piperidinecarbonitrile | C25H29N3 | 详情 | 详情 | |
| (XI) | 51997 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-(formylanilino)-4-piperidinecarboxamide | C26H31N3O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)The title compound was synthesized by two related methods. Stobbe condensation between 4-hydroxybenzaldehyde (I) and diethyl succinate (II) in the presence of NaOEt afforded the benzylidenesuccinate monoester (III). Coupling of (III) with cis-hexahydroisoindoline (IV) gave the amidoester (V). The phenolic hydroxyl group of (V) was then alkylated with tosylate (VI) to provide the corresponding ether (IX). Alternatively, intermediate (IX) was obtained by initial alkylation of 4-hydroxybenzaldehyde (I) with tosylate (VI). The resultant alkyloxy benzaldehyde (VII) was then subjected to Stobbe condensation with diethyl succinate (II) to afford the benzylidenesuccinate (VIII), which was further coupled with the bicyclic amine (IV) to produce (IX). Finally, ester (IX) obtained by either synthetic method was hydrolyzed with NaOH to furnish the target carboxylic acid.
| 【1】 Kitajima, H.; et al.; Hybridization of non-sulfonylurea insulin secretagogue and thiazolidinedione-derived insulin sensitizer. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 37. |
| 【2】 Kitajima, H.; et al.; Hybridization of non-sulfonylurea insulin secretagogue and thiazolidinedione-derived insulin sensitizer. Bioorg Med Chem Lett 2000, 10, 21, 2453. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 51544 | (E)-3-(ethoxycarbonyl)-4-(4-hydroxyphenyl)-3-butenoic acid | C13H14O5 | 详情 | 详情 | |
| (IV) | 41059 | (3aR,7aS)octahydro-1H-isoindole | C8H15N | 详情 | 详情 | |
| (V) | 51545 | ethyl (E)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-(4-hydroxyphenyl)-2-propenoate | C21H27NO4 | 详情 | 详情 | |
| (VI) | 51546 | 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl 4-methylbenzenesulfonate | C19H19NO4S | 详情 | 详情 | |
| (VII) | 51547 | ethyl (E)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-2-propenoate | C33H38N2O5 | 详情 | 详情 | |
| (VIII) | 19732 | tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropylcarbamate | C31H46N4O5 | 详情 | 详情 | |
| (IX) | 51548 | (E)-3-(ethoxycarbonyl)-4-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]-3-butenoic acid | C25H25NO6 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Claisen condensation between diethyl phthalate (I) and diethyl succinate (II) in the presence of NaOEt gives rise to the naphthalenedicarboxylate (III). Alkylation of the phenolic hydroxyl groups of (III) with iodoethane under Williamsom's ether synthesis conditions furnishes the diethoxy napthalenedicarboxylate (IV). Then, alkaline hydrolysis of diester (IV) affords diacid (V), which is further converted to the cyclic anhydride (VI) upon treatment with SOCl2. Condensation of anhydride (VI) with ethyl p-aminophenylacetate (VII) in boiling AcOH leads to the cyclic imide (VIII). Partial reduction of (VIII) with Zn/AcOH produces lactam (IX). The ethyl ester group of (IX) is then selectively hydrolyzed under alkaline conditions to furnish acid (X). Finally, CDI-mediated coupling of acid (X) with benzesulfonamide yields the target N-acyl sulfonamide.
| 【1】 Giblin, G.M.P.; Foord, S.; Wilson, R.; et al.; Novel nonprostanoid prostaglandin EP4 receptor antagonist. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 306. |
| 【2】 Frye, S.V.; Giblin, G.M.P.; Roomans, S. (GlaxoSmithKline plc); Benzo(f)isoindol derivs. and their use as EP4 receptor ligands. WO 0250033 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 60866 | diethyl phthalate | C12H14O4 | 详情 | 详情 | |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 60867 | diethyl 1,4-dihydroxy-2,3-naphthalenedicarboxylate | C16H16O6 | 详情 | 详情 | |
| (IV) | 60868 | diethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate | C20H24O6 | 详情 | 详情 | |
| (V) | 60869 | 1,4-diethoxy-2,3-naphthalenedicarboxylic acid | C16H16O6 | 详情 | 详情 | |
| (VI) | 60870 | 4,9-diethoxynaphtho[2,3-c]furan-1,3-dione | C16H14O5 | 详情 | 详情 | |
| (VII) | 21230 | ethyl 2-(4-aminophenyl)acetate | 5438-70-0 | C10H13NO2 | 详情 | 详情 |
| (VIII) | 60871 | ethyl 2-[4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate | C26H25NO6 | 详情 | 详情 | |
| (IX) | 60872 | ethyl 2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate | C26H27NO5 | 详情 | 详情 | |
| (X) | 60873 | 2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid | C24H23NO5 | 详情 | 详情 |